Aging is associated with the development of vascular endothelial dysfunction characterized by impaired endothelium-dependent dilation (EDD), an independent predictor of cardiovascular disease risk. Although impaired EDD is associated with oxidative stress and chronic low-grade inflammation, the mechanisms by which these processes develop with aging and strategies that can be employed to prevent them are incompletely understood. One unexplored hypothesis is that impairments in the regulation and/or cellular machinery of autophagy underlie the development of vascular endothelial dysfunction (reduced EDD) with aging. Autophagy, the major process by which cells catabolize damaged macromolecules and organelles, inhibits oxidative stress and inflammation and is associated with enhanced longevity. However, its potential role in mediating age-associated vascular endothelial dysfunction is entirely unknown. Accordingly, the goal of this research training project is to determine the role of autophagy in age-related vascular endothelial dysfunction, and to establish the efficacy of an intervention for restoring function. To accomplish this, I will use a novel integrative translational experimental approach that links biochemical and physiological (functional) observations in vitro, ex vivo and in vivo. Specifically, I will assess age-related differences in markers/regulators of autophagy and vascular endothelial function in cell culture, mice, and human subjects. I will also examine relations between autophagy, EDD and oxidative stress/inflammation. Finally, I will determine the efficacy of an intervention designed to stimulate autophagy and restore endothelial function with aging in mice. These results will provide novel and clinically important insight regarding the mechanisms mediating the age-related decline in vascular endothelial function. PUBLIC HEALTH RELEVANCE: Aging is associated with the development of vascular endothelial dysfunction, an important predictor of cardiovascular disease, but the mechanisms underlying this process are incompletely understood. One unexplored hypothesis is that impairments in autophagy, an important cellular "housekeeping" process, underlie the development of vascular endothelial dysfunction with aging. This translational research project is designed to assess the role of autophagy in age-related vascular endothelial dysfunction in cells, mice and humans, and it will provide novel and clinically important insight into related mechanisms and potential preventative strategies.